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WO2023024949A1 - Conjugué anticorps-médicament conjugué par l'intermédiaire d'un lieur cassable - Google Patents

Conjugué anticorps-médicament conjugué par l'intermédiaire d'un lieur cassable Download PDF

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Publication number
WO2023024949A1
WO2023024949A1 PCT/CN2022/112502 CN2022112502W WO2023024949A1 WO 2023024949 A1 WO2023024949 A1 WO 2023024949A1 CN 2022112502 W CN2022112502 W CN 2022112502W WO 2023024949 A1 WO2023024949 A1 WO 2023024949A1
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Prior art keywords
pharmaceutically acceptable
stereoisomer
acceptable salt
compound
antibody
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PCT/CN2022/112502
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English (en)
Chinese (zh)
Inventor
丁会
于海勇
许云雷
劳芳
刘岩
张西东
荣鹏飞
柯天一
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昆山新蕴达生物科技有限公司
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Priority to EP22860295.9A priority Critical patent/EP4393514A1/fr
Priority to CN202280057594.2A priority patent/CN117881431A/zh
Priority to JP2024512107A priority patent/JP2024532295A/ja
Publication of WO2023024949A1 publication Critical patent/WO2023024949A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants

Definitions

  • the present disclosure relates to antibody drug conjugates (ADCs) that bind human oncology antigen targets and/or provide anti-tubulin drug activity.
  • ADCs antibody drug conjugates
  • the present disclosure further relates to methods and compositions useful for treating cancers that express tumor antigen targets and/or are treatable by disrupting tubulin.
  • antibody-drug conjugates obtained by coupling monoclonal antibodies to toxin small molecules have become a hot spot in tumor-targeted therapy.
  • Antibody-drug conjugates (antibody-drug conjugates, ADCs) connect biologically active small-molecule drugs to monoclonal antibodies through a chemical link, and monoclonal antibodies serve as carriers to target and transport small-molecule drugs into target cells.
  • Research on ADC can be traced back to the 1980s, but it was not until 2000 that the first antibody-conjugated drug (trade name Mylotarg, developed by Pfizer) was approved by the FDA for the treatment of acute myeloid leukemia, and the fatal toxicity caused by immature technology was Withdrawal from the market in 2010.
  • brentuximabvedotin SGN-35, trade name Adcetris
  • Ado-trastuzumabemtansine T-DM1, trade name Kadcyla
  • Genentech/ImmunoGen was approved by the FDA for HER2-positive breast cancer, becoming the first antibody-conjugated drug for solid tumors.
  • ADCs there are 12 kinds of ADCs that have been approved for marketing, and the products whose effects have attracted attention include IMMU-132, Daiichi Sankyo's ds-8210a, etc.
  • ADC consists of antibodies, small molecule toxins and linkers. Small-molecule toxins are covalently coupled to antibodies through linkers; antibodies (such as monoclonal antibodies) can specifically recognize specific targets on the surface of tumor cells, and then guide ADCs to reach the surface of cancer cells, and allow ADCs to be internalized and absorbed. Kill tumor cells.
  • the small-molecule toxins used in ADC are divided into two categories: DNA damage agents and microtubule inhibitors.
  • the former includes camptothecins, and the latter includes dolastatin and its auristatins derivatives (MMAE, MMAF, MMAD).
  • MMAE, MMAF, MMAD dolastatin and its auristatins derivatives
  • DM1, DM2, DM3, DM4 maytansine and maytansinoid derivatives maytansinoids.
  • the small molecule toxin used by Kadcyla is DM1.
  • Eribulin belongs to the class of tubulin polymerization inhibitors, which is a synthetic analog of halichondrin (halichondrin B), a substance discovered from black sponges that grow off the coast of Japan, in 2010 Approved by the US FDA for the first time for the treatment of metastatic breast cancer, it can effectively cure the tumor, and it is the only single-drug chemotherapy drug. In addition to its remarkable therapeutic effect on metastatic breast cancer, Eribulin can be used for multiple indications, so its late-stage development space is huge, and it is a drug with great ADC development value.
  • One of the most common attachment sites on antibodies for ADC conjugation is lysine, whose ⁇ -amino group can react with the activated carboxyl group of the linker to form an amide bond.
  • amide bonds are prone to hydrolysis under the action of enzymes in the body, resulting in the shedding of bioactive molecules and antibodies before reaching the target cells, which increases the toxicity while losing the targeting of ADC.
  • Another common attachment site is a cysteine residue.
  • the sulfur groups of antibody cysteine exist in the form of disulfide bonds. Opening disulfide bonds in antibodies can provide multiple free sulfhydryl groups as conjugation sites.
  • one method is Michael addition reaction between the free sulfhydryl group on the antibody and maleimide, or a specific substrate and the free sulfhydryl group on the antibody through two Michael addition reactions to form A structurally unique sulfur bridge.
  • Michael addition reaction between the free sulfhydryl group on the antibody and maleimide, or a specific substrate and the free sulfhydryl group on the antibody through two Michael addition reactions to form A structurally unique sulfur bridge.
  • the small molecule toxin eribulin is at least 10 times more toxic than DNA-damaging toxoids such as camptothecin derivatives, so when developing ADC drugs targeting eribulin, it is It is more necessary to consider the issue of its safety.
  • ADC drugs targeting eribulin it is It is more necessary to consider the issue of its safety.
  • the antibody-drug conjugate containing a novel linker structure through the antibody-drug conjugate containing a novel linker structure, a high drug loading capacity is achieved, and at the same time, a faster onset time, longer drug half-life, excellent stability, good biocompatibility, and low immune Antibody-drug conjugates with good originality and safety.
  • the antibody-drug conjugate of the present invention exhibits excellent antitumor effects.
  • the first aspect of the present disclosure provides the compound represented by formula (I), its pharmaceutically acceptable salt, its stereoisomer, or the solvent of said compound, its pharmaceutically acceptable salt or its stereoisomer compound,
  • MC is
  • L is a peptide residue selected from glycine-glycine-phenylalanine-glycine (GGFG), valine-citrulline (VC), valine-alanine (VA),
  • L 2 is selected from single bond, -NH-CH 2 -,
  • D is a drug linked to L2 through a chemical bond, and the drug is selected from eribulin or its derivatives, gemotecan, gemotecan, and SN-38.
  • L is selected from:
  • L is selected from:
  • L is GGFG or L 2 is selected from single bond, -NH-CH 2 -,
  • L 1 is GGFG
  • L 2 is selected from a single bond, -NH-CH 2 -,
  • L is VC or L2 is selected from single bond
  • L 1 is VC
  • L 2 is selected from a single bond
  • L is VA or (preferably VA or ), L 2 is selected from single bond,
  • L 1 is VA and L 2 is selected from a single bond
  • D is eribulin or a derivative thereof.
  • D has the structural formula
  • the compound shown in formula (I) is selected from:
  • the compound of formula (I) can be used as a linker-drug intermediate compound for the synthesis of antibody-drug conjugates. Compared with linker-drug intermediate compounds in the prior art (for example, some linker-drug intermediate compounds with self-breaking bonds), the compound of formula (I) has the advantages of simple synthesis and stable structure.
  • the second aspect of the present disclosure provides an antibody-drug conjugate, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or the conjugate, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof
  • the solvate of the isomer can be formed by linking the targeting moiety with the compound represented by formula (I) through a thioether bond.
  • the antibody-drug conjugate has a structure as shown in formula (II)
  • Ab is a targeting moiety selected from antibodies, antibody fragments, or antibody-based molecules or compounds;
  • p is an integer selected from 1-20, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 , 20, for example, an integer selected from 1-8.
  • the Ab targeting moiety is an antibody, antibody fragment, bispecific or other multivalent antibody, or other antibody-based molecule or compound.
  • Antibodies may be of various isotypes, preferably human IgGl, IgG2, IgG3 or IgG4, more preferably comprising human IgGl hinge and constant region sequences.
  • Antibodies or fragments thereof may be chimeric human-mouse, chimeric human-primate, humanized (human framework and murine hypervariable (CDR) regions) or fully human antibodies and variants thereof, such as half IgG4 antibodies (referred to as "single antibody”), as described by van der Neut Kolfschoten et al. (Science 2007; 317:1554-1557).
  • antibodies or fragments thereof can be designed or selected to comprise human constant region sequences belonging to a particular allotype, which can result in reduced immunogenicity when the antibody or immunoconjugate is administered to a human subject.
  • Preferred allotypes for administration include non-G1m1 allotypes (nG1m1), such as G1m3, G1m3,1, G1m3,2 or G1m3,1,2. More preferably, the allotype is selected from the group consisting of nG1m1, G1m3, nG1m1,2 and Km3 allotypes.
  • Suitable antibodies can bind any disease-associated antigen known in the art.
  • the disease state is cancer
  • a number of antigens expressed by or otherwise associated with tumor cells are known in the art, including but not limited to carbonic anhydrase IX, alpha-fetoprotein , AFP), ⁇ -actinin-4 ( ⁇ -actinin-4), A3, antigen specific to A33 antibody, ART-4, B7, Ba 733, BAGE, BrE3 antigen, CA125, CAMEL, CAP -1, CASP-8/m,, CCL19, CCL21, CD1, CD1a, CD2, CD3, CD4, CD5, CD8, CD11A, CD14, CD15, CD16, CD18, CD19, CD20, CD21, CD22, CD23, CD25, CD29, CD30, CD32b, CD33, CD37, CD38, CD40, CD40L, CD44, CD45, CD46, CD52, CD54, CD55, CD59, CD64, CD66a-e, CD67
  • IGF-1 insulin-like growth factor 1
  • IGF-1R insulin-like growth factor 1
  • KS1-4 insulin-like
  • RS5 RANTES, T101, SAGE, S100, survivin, survivin-2B, TAC, TAG-72, tenascin, TRAIL receptor, TNF- ⁇ , Tn antigen, Thomson- Fredenrich antigen (Thomson-Friedenreich antigen), tumor necrosis antigen, VEGFR, ED-B fibronectin (fibronectin), WT-1, 17-1A antigen, complement factor C3, C3a, C3b, C5a, C5, Angiogenesis markers, bcl-2, bcl-6, Kras, oncogene markers and oncogene products (see e.g.
  • the antibody binds her2, her3, claudin 18.2, ROR-1, dll-3, mucl, muc-17, EGP-1 (Trop-2).
  • Exemplary antibodies that may be utilized include, but are not limited to, hR1 (anti-IGF-1R, U.S. Patent No. 13/688,812), hPAM4 (anti-Mucin, U.S. Patent No. 7,282,567), hA20 (anti-CD20, U.S. Patent No. 7,151,164), hA19 ( Anti-CD19, U.S. Patent No. 7,109,304), hIMMU31 (anti-AFP, U.S. Patent No. 7,300,655), hLL1 (anti-CD74, U.S. Patent No. 7,312,318), hLL2 (anti-CD22, U.S. Patent No.
  • the antibody is IMMU-31 (anti-AFP), hRS7 (anti-Trop-2), hMN-14 (anti-CEACAM5), hMN-3 (anti-CEACAM6), hMN-15 (anti-CEACAM6), hLL1 (anti-CD74 ), hLL2 (anti-CD22), hL243 or IMMU-114 (anti-HLA-DR), hA19 (anti-CD19) or hA20 (anti-CD20).
  • the terms epratuzumab and hLL2 are interchangeable, as are the terms veltuzumab and hA20, hL243g4P, hL243 ⁇ 4P, and IMMU-114.
  • the antibody is anti-Trop-2 antibody such as hRS7; anti-ROR1 antibody such as 99961 (Chinese Patent No. 104662044); anti-HER-3 antibody such as patritumab (Chinese Patent No. 102174105); anti-HER2 antibody Herceptin (Trastuzumab), Pertuzumab.
  • Suitable alternative antibodies include, but are not limited to, abciximab (anti-glycoprotein IIb/IIIa), alemtuzumab (anti-CD52), bevacizumab (anti-VEGF), Western Cetuximab (anti-EGFR), gemtuzumab (anti-CD33), ibritumomab (anti-CD20), panitumumab (anti-EGFR), Rituximab (anti-CD20), tositumomab (anti-CD20), trastuzumab (anti-ErbB2), lambrolizumab (anti-PD1 receptor ), atezolizumab (anti-PD-L1), MEDI4736 (anti-PD-L1), nivolumab (anti-PD-1 receptor), ipilimumab (anti-PD-1 CTLA-4), abagovomab (anti-CA-125), adecatumumab (anti-EpCAM), atlizumab (anti
  • the drug moiety conjugated to the subject antibody is selected from eribulin or a derivative thereof, eg, the mesylate salt of eribulin.
  • eribulin refers to a synthetic analog of halichondrin B, a macrocyclic compound originally isolated from the sponge Halichondria okadais. Eribulin is a microtubule inhibitor that is thought to bind tubulin and cause cell cycle arrest in G2/M phase by inhibiting mitotic spindle assembly.
  • eribulin mesylate refers to the mesylate salt of eribulin, which is sold under the tradename Halaven TM .
  • the drug part can also choose a camptothecin compound or its derivatives, such as gemitecan, gemotecan or SN-38, whose structural formulas are as follows:
  • the drug part can also choose DXD, whose structural formula is as follows:
  • the antibody or fragment thereof is linked to at least one chemotherapeutic moiety; for example 1 to 5 (eg 1, 2, 3, 4 or 5) drug moieties, 5 to 8 (eg 5, 6 , 7 or 8) drug moieties or 8 to 12 (eg 8, 9, 10, 11 or 12) drug moieties.
  • chemotherapeutic moiety for example 1 to 5 (eg 1, 2, 3, 4 or 5) drug moieties, 5 to 8 (eg 5, 6 , 7 or 8) drug moieties or 8 to 12 (eg 8, 9, 10, 11 or 12) drug moieties.
  • the present disclosure provides the compound, pharmaceutically acceptable salt, stereoisomer or solvate of the first aspect, and the antibody-drug conjugate and pharmaceutically acceptable salt of the second aspect , A method for the preparation of a stereoisomer or a solvate.
  • the method includes the following steps:
  • An exemplary synthesis process is as follows: Eribulin and DIEA are added to a DMF solution of compound i, and the reaction solution is stirred at room temperature.
  • the method comprises the following steps:
  • the compound ii is condensed with eribulin in the presence of DIEA/HATU to generate the compound represented by formula (I).
  • An exemplary synthesis process is as follows: compound ii, eribulin and HATU are dissolved in DMF, DIEA is added at room temperature, and the reaction solution is stirred at room temperature.
  • the method comprises the following steps:
  • the compound iii is condensed with eribulin in the presence of DIEA/HATU to generate the compound represented by formula (I).
  • An exemplary synthesis process is as follows: compound iii, eribulin and HATU are dissolved in DMF, DIEA is added at room temperature, and the reaction solution is stirred at room temperature.
  • an antibody-drug conjugate in which an antibody and a linker structure are linked via a thioether can be produced by the following method.
  • the antibody-drug conjugate represented by formula (II) is described in the form of a structure in which one structural part from the drug to the end of the linker is linked to one antibody, but in fact, relatively A plurality of such structural parts are often linked to one antibody molecule.
  • 2 to 8, preferably 4 to 8, and more preferably 6 to 8 linker-drug intermediate compounds are linked to one antibody molecule.
  • the average number of linker-drugs linked to each antibody molecule is represented by the average number of drug links.
  • the antibody-drug conjugate represented by the formula (II) can be produced by reacting the above-mentioned linker-drug intermediate compound of the present invention with the antibody Ab-SH having a sulfhydryl group.
  • a reducing agent 1 to 7 molar equivalents of TCEP are used per one hinge disulfide bond in the antibody, and reacted with the antibody in a buffer containing the chelating agent EDTA, thereby obtaining a partial Or an antibody (AB-SH) carrying a sulfhydryl group obtained by completely reducing the disulfide in the hinge part of the antibody.
  • a chelating agent ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), etc. are mentioned, for example. They can be used at a concentration of 1 mM to 20 mM.
  • the buffer solution sodium phosphate, sodium borate, sodium acetate solution or the like can be used.
  • antibody AB-SH having a sulfhydryl group can be obtained by reacting the antibody with TCEP at 4°C to 37°C for 1 to 4 hours.
  • each antibody Ab-SH having a sulfhydryl group 2 to 20 molar equivalents of the compound represented by formula (I) can be used to produce an antibody-drug conjugate in which one antibody is linked with two to eight drugs ( II).
  • a solution in which the compound represented by the formula (I) is dissolved is added to a buffer containing the antibody Ab-SH having a sulfhydryl group, and reacted.
  • the buffer sodium acetate solution, sodium phosphate, sodium borate, or the like can be used as the buffer.
  • the pH at the time of reaction is 5-9, and it is more preferable to react around pH7.
  • organic solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMA), and N-methyl-2-pyridone (NMP) can be used .
  • DMSO dimethylsulfoxide
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • NMP N-methyl-2-pyridone
  • the organic solvent solution in which the compound represented by the formula (I) is dissolved is added to the buffer containing the antibody Ab-SH having a sulfhydryl group at 1 to 20% v/v, and reacted.
  • the reaction temperature is 0-37°C, more preferably 10-25°C, and the reaction time is 0.5-2 hours.
  • the reaction can be terminated by inactivating the reactivity of the unreacted compound represented by formula (I) with a thiol-containing reagent.
  • Thiol-containing reagents are, for example, cysteine or N-acetyl-L-cysteine (NAC). More specifically, the reaction is completed by adding 1 to 2 molar equivalents of cysteine to the compound represented by the formula (I) used and incubating at room temperature for 10 to 30 minutes.
  • cysteine or N-acetyl-L-cysteine (NAC). More specifically, the reaction is completed by adding 1 to 2 molar equivalents of cysteine to the compound represented by the formula (I) used and incubating at room temperature for 10 to 30 minutes.
  • centrifuge to perform centrifugation (for example, centrifuge at 2000G-3800G for 5-20 minutes) to concentrate the antibody or antibody-drug conjugate solution.
  • Antibody concentration was measured using a UV analyzer according to the method specified by the manufacturer.
  • phosphate buffer e.g. PBS
  • sodium chloride e.g., 137 mM
  • EDTA ethylenediaminetetraacetic acid
  • a PD-10 column using Sephadex G-25 carrier was equilibrated.
  • 1 mL of an antibody aqueous solution was loaded, and then a fraction (3.5 mL) eluted with PBS/EDTA 2 mL was separated. This fraction was concentrated by common procedure A, and the antibody concentration was measured by common procedure B, and then adjusted to 10 mg/mL using PBS/EDTA.
  • Phosphate buffer eg, 50 mM, pH 6.5, also referred to as PBS6.5/EDTA in this specification
  • sodium chloride eg, 50 mM
  • EDTA eg, 2 mM
  • a PD-10 column using Sephadex G-25 carrier was equilibrated.
  • 1 mL of antibody aqueous solution was loaded, and then the fraction (3.5 mL) eluted with PBS6.5/EDTA 2 mL was separated and obtained. This fraction was concentrated by common procedure A, and the antibody concentration was measured by common procedure B, and then the antibody concentration was adjusted to 5 mg/mL using PBS6.5/EDTA.
  • phosphate buffer eg, PBS7.4
  • sodium phosphate buffer eg, 10 mM, pH6.5; also referred to as PBS6.5 in this specification
  • Acetic acid buffer e.g., 10 mM, pH 5.5; also referred to as ABS in this specification
  • sorbitol e.g., 5%
  • An antibody-drug conjugate reaction aqueous solution (for example, about 1 mL) was packed in this column, and the antibody fraction was separated and obtained by eluting with an amount of buffer solution specified by the manufacturer.
  • Drug linkers, antibody-drug conjugates of low molecular weight compounds tris(2-carboxyethyl)phosphine hydrochloride (TCEP), cysteine, dimethyl sulfoxide, etc.
  • Phosphate buffer eg, PBS7.4
  • sodium phosphate buffer eg, 10 mM, pH6.5; also referred to as PBS6.5 in this specification
  • sodium chloride eg, 137 mM
  • sorbitol-containing for example, 5%
  • acetate buffer for example, 10mM, pH5.5; also referred to as ABS in this specification
  • MES 25mM pH6.5 or any buffer solution in His 10mM pH 5.5 AKTA column ( Filler: Sephadex G 25) Balanced.
  • the injector is loaded with an antibody-drug conjugate reaction aqueous solution (for example, about 2 mL), and eluted with an amount of buffer solution specified by the manufacturer, thereby separating and obtaining antibody fractions.
  • an antibody-drug conjugate in which unlinked drug linkers and low-molecular compounds (tris(2-carboxyethyl)phosphine hydrochloride (TCEP), cysteine, dimethyl sulfoxide, etc.) were removed was obtained. United things.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound, pharmaceutically acceptable salt, stereoisomer, or solvate described in the first aspect, or the conjugated compound described in the second aspect substances, pharmaceutically acceptable salts, stereoisomers, or solvates, and one or more pharmaceutical adjuvants, such as carriers and/or excipients.
  • the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form.
  • the pharmaceutical composition may also be administered to an individual in need of such treatment by any suitable means of administration, such as oral, parenteral, rectal or pulmonary administration.
  • the pharmaceutical composition can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions , syrup, etc.
  • suitable fillers, binders, disintegrants, lubricants and the like can be added.
  • parenteral administration the pharmaceutical composition can be made into injections, including injections, sterile powders for injections and concentrated solutions for injections.
  • the pharmaceutical composition When making injections, it can be produced by conventional methods in the existing pharmaceutical field. When preparing injections, no additives can be added, and suitable additives can also be added according to the properties of the medicine.
  • the pharmaceutical composition For rectal administration, the pharmaceutical composition can be made into suppositories and the like.
  • the pharmaceutical composition When used for pulmonary administration, can be made into inhalants or sprays and the like.
  • the present disclosure provides the compound, pharmaceutically acceptable salt, stereoisomer, or solvate described in the first aspect, or the conjugate, pharmaceutically acceptable salt, Use of stereoisomers or solvates in the preparation of medicines for treating diseases related to abnormal cell activity (such as cancer diseases).
  • the present disclosure provides the compound, pharmaceutically acceptable salt, stereoisomer, or solvate described in the first aspect, or the conjugate, pharmaceutically acceptable salt, Stereoisomers, or solvates, or the use of the pharmaceutical composition of the fourth aspect for treating diseases related to abnormal cell activity (such as cancer diseases).
  • the present disclosure provides a method for treating a disease related to abnormal cell activity (such as cancer disease), including providing an effective dose of the present disclosure to an individual in need of the compound described in the first aspect, a pharmaceutically acceptable salt , stereoisomer, or solvate, or the conjugate, pharmaceutically acceptable salt, stereoisomer, or solvate of the second aspect, or the pharmaceutical composition of the fourth aspect.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage values may vary with the type and severity of the condition to be alleviated and may comprise single or multiple doses. It is further understood that for any given individual, the particular dosing regimen may be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • Various embodiments may relate to using the subject methods and compositions to treat cancer, including but not limited to metastatic breast cancer, non-small cell lung cancer, Burkitt lymphoma, Hodgkin's lymphoma, acute myeloid Leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytes, skin cancer, oral cancer, esophagus cancer, gastrointestinal tract cancer, lung cancer, lung cancer, stomach cancer, colon cancer, rectal cancer, triple-negative breast cancer, Ovarian cancer, prostate cancer, uterine cancer, endometrial cancer, cervical cancer, bladder cancer, pancreatic cancer, bone cancer, brain cancer, connective tissue cancer, thyroid cancer, liver cancer, gallbladder cancer, bladder (urothelial) cancer, kidney cancer, skin cancer, central nervous system cancer and testicular cancer.
  • metastatic breast cancer non-small cell lung cancer, Burkitt lymphoma, Hodgkin's lymphoma, acute myeloid Leukemia, chronic myelogenous leuk
  • the antibody or immunoconjugate can be combined with surgery, radiation therapy, chemotherapy, immunotherapy with naked antibodies including checkpoint inhibitory antibodies, radioimmunotherapy, immunomodulators, vaccines and other combinations.
  • the antibody or immunoconjugate is used in combination with a PARP inhibitor, microtubule inhibitor, Bruton kinase inhibitor and/or PI3K inhibitor.
  • combination therapies may allow lower doses of each therapeutic agent to be administered in the context of the combination, thus reducing certain serious side effects and potentially reducing the required course of treatment.
  • the full doses of each can also be administered in the absence or presence of minimal overlapping toxicity.
  • the antibody or immunoconjugate can be administered as a periodic bolus injection, in alternative embodiments, the antibody or immunoconjugate can be administered by continuous infusion.
  • continuous infusion can be administered, eg, through an indwelling catheter.
  • indwelling catheter Such devices are known in the art, such as or catheter (see, eg, Skolnik et al., The Drug Monit 32:741-48, 2010), and any such known indwelling catheter can be used.
  • a variety of continuous infusion pumps are also known in the art, and any such known infusion pump can be used. Dosages for continuous infusion may range between 0.1 and 3.0 mg/kg per day. More preferably, these immunoconjugates are administered by intravenous infusion over a relatively brief period of 2 to 5 hours, more preferably 2-3 hours.
  • the antibody or immunoconjugate and schedule of administration may be effective in patients resistant to standard therapy.
  • hRS7-eribulin immunoconjugates can be administered to patients who have not responded to previous therapy with eribulin.
  • irinotecan-resistant patients can show partial or even complete responses to hRS7-eribulin.
  • the ability of immunoconjugates to specifically target tumor tissue can overcome tumor resistance due to improved targeting and enhanced delivery of therapeutic agents.
  • a particularly preferred subject may have Trop-2 positive breast cancer, ovarian cancer, cervical cancer, endometrial cancer, lung cancer, prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder (urothelial) cancer , kidney cancer, pancreatic cancer, brain cancer, thyroid cancer, epithelial cancer, or head and neck cancer.
  • the cancer is metastatic cancer. More preferably, the patient has previously failed treatment with at least one standard anticancer therapy.
  • the cancer is metastatic breast cancer, TNBC, non-TNBC, endometrial cancer, lung cancer, ovarian cancer or colon cancer.
  • the present disclosure provides a pharmaceutical preparation comprising the compound, pharmaceutically acceptable salt, stereoisomer, or solvate described in the first aspect, or the conjugate described in the second aspect , a pharmaceutically acceptable salt, stereoisomer, or solvate, or the pharmaceutical composition of the fourth aspect.
  • the present disclosure provides the compound, pharmaceutically acceptable salt, stereoisomer, or solvate described in the first aspect, or the conjugate or pharmaceutically acceptable salt described in the second aspect , stereoisomers, or solvates, or the pharmaceutical composition of the fourth aspect for the preparation of pharmaceutical preparations.
  • the present disclosure provides a kit comprising the compound, pharmaceutically acceptable salt, stereoisomer, or solvate described in the first aspect, or the conjugate described in the second aspect , a pharmaceutically acceptable salt, stereoisomer, or solvate, or the pharmaceutical composition of the fourth aspect, or the pharmaceutical preparation of the eighth aspect.
  • the compounds, conjugates, pharmaceutically acceptable salts, stereoisomers, or solvates, pharmaceutical preparations or kits provided in this disclosure can be used to inhibit the growth, proliferation or migration of cancer cells.
  • the compounds, conjugates, pharmaceutically acceptable salts, stereoisomers, or solvates, pharmaceutical formulations or kits are for in vivo or in vitro administration; e.g., administered into a subject, or administered in vitro Cells (eg cell lines or cells from an individual such as cancer cells).
  • the present disclosure provides a method for inhibiting the growth, proliferation or migration of cancer cells, which comprises administering to cancer cells an effective amount of the compound, pharmaceutically acceptable salt, stereoisomeric Conformer, or solvate, or the conjugate, pharmaceutically acceptable salt, stereoisomer, or solvate described in the second aspect, or the pharmaceutical composition of the fourth aspect, or the pharmaceutical composition of the eighth aspect Pharmaceutical preparations.
  • linker refers to a chemical structural fragment or bond that is connected to an antibody at one end and a drug (drug compound) at the other end, and other linkers can also be connected It is then linked to a drug compound.
  • linker structure of the present invention can be synthesized by methods known in the art, and can also be synthesized using the methods described in the present invention.
  • the "antibody-drug conjugate" in the present invention refers to a targeting moiety such as an antibody or an antigen-binding fragment thereof linked to a biologically active drug through a stable linker unit.
  • pharmaceutically acceptable salt refers to a relatively non-toxic acid addition salt or base addition salt of the compound or conjugate of the present invention.
  • the acid addition salt is a salt formed between the compound or conjugate of the present invention and a suitable inorganic acid or organic acid, and these salts can be prepared by making the compound or conjugate of the present invention and a suitable organic acid or inorganic acid prepared by reacting in a solvent.
  • Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate Salt, Luurosilicate, Borate, Benzoate, Lactate, Nitrate, Phosphate, Phosphate, Carbonate, Bicarbonate, Toluate, Citrate, Maleic Acid Salt, fumarate, succinate, malate, ascorbate, tannate, pamoate, alginate, naphthalenesulfonate, tartrate, benzoate, methanesulfonate, p-toluene Sulfonate, Gluconate, Lactobionate and Lauryl Sulfonate etc.
  • the base addition salt is a salt formed between the compound or conjugate of the present invention and a suitable inorganic base or organic base, and these salts can be obtained by making the compound or conjugate of the present invention and a suitable inorganic base or organic base prepared by reacting in a solvent.
  • Representative base addition salts include, for example, salts with alkali metal, alkaline earth metal, quaternary ammonium cations, such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium Salts, etc.; amine salts, including salts formed with ammonia (NH 3 ), primary amines, secondary amines or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.
  • quaternary ammonium cations such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium Salts, etc.
  • amine salts including salts formed with ammonia (NH 3 ), primary amines, secondary amines or tertiary amines, such as methylamine
  • the compounds or conjugates of the present invention can exist in specific geometric or stereoisomer forms.
  • the chiral center can exist in the drug, in the linker structure, or in the Antibodies and their derivatives.
  • all such compounds including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are included in the present invention within the range.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound or conjugate of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • solvates such as hydrates of the compounds, conjugates, pharmaceutically acceptable salts, and stereoisomers of the present invention are also within the scope of the present invention.
  • suitable solvates specifically, solvates formed between compounds or conjugates of the present invention and acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether, etc. . Hydrates or ethanolates are also mentioned.
  • treating an individual suffering from a disease or condition means that the individual's symptoms are partially or completely relieved, or remain unchanged after treatment.
  • treatment includes prophylaxis, treatment and/or cure.
  • Prevention refers to preventing an underlying disease and/or preventing worsening of symptoms or development of a disease.
  • Treatment or prevention also includes any pharmaceutical use of the provided ADCs and the pharmaceutical compositions, pharmaceutical formulations provided herein.
  • the term “effective dose” refers to the amount of a compound which, when administered, alleviates to some extent one or more symptoms of the condition being treated. Similarly, the term “effective amount” refers to the amount of a compound which, when administered, inhibits the growth, proliferation or migration of cancer cells to some extent.
  • therapeutic effect means the effect resulting from the treatment of an individual, which alters, usually ameliorates or improves the symptoms of a disease or condition, or cures the disease or condition.
  • “individual” includes human or non-human animal.
  • exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).
  • compositions and methods are not to be limited to the particular compositions and methods described and/or illustrated herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting. Compositions and methods claimed.
  • compositions and methods of using the compositions refers to compositions and methods of using the compositions.
  • present disclosure describes or claims features or embodiments in relation to a composition, such features or embodiments apply equally to methods of using said compositions.
  • present disclosure describes or claims a feature or embodiment in relation to a method of using the composition, such feature or embodiment applies equally to said composition.
  • compositions and methods which are described herein in the context of separate embodiments, are, for clarity, also provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.
  • Figure 1 shows the SEC-HPLC results of ADC-1 synthesized in Example 2.
  • FIG. 1 shows the SEC-HPLC results of ADC-2 synthesized in Example 3.
  • FIG. 3 shows the SEC-HPLC results of ADC-3 synthesized in Example 4.
  • FIG. 4 shows the SEC-HPLC results of ADC-4 synthesized in Example 5.
  • Fig. 5 is the statistical curve of the antitumor activity of Example 6.
  • Fig. 6 is the body weight change curve of embodiment 6.
  • FIG. 7 is a photograph of the tumor taken in Example 6.
  • Fig. 8 is the statistical curve of the anti-tumor activity of Example 7.
  • Figure 9 is the body weight change curve of Example 7.
  • Fig. 10 is a photogram of the tumor taken in Example 7.
  • Fig. 11 is the statistical curve of the anti-tumor activity of Example 8.
  • Figure 12 is the body weight change curve of Example 8.
  • Figure 13 is the statistical curve of the anti-tumor activity of Example 9.
  • Figure 14 is the body weight change curve of Example 9.
  • Fig. 15 is a picture taken of the tumor taken in Example 9.
  • hRS7 antibody was produced in CHO cells.
  • the expression vectors containing the hRS7 antibody gene were constructed by conventional molecular biology methods.
  • the amino acid sequences of the hRS7 antibody light chain and heavy chain are shown in SEQ ID NO: 1 and SEQ ID NO: 2 respectively, and the corresponding nucleotide sequences Shown in SEQ ID NO:3 and SEQ ID NO:4 respectively.
  • Insert the above two sequences into the same expression vector extract a large number of transfection plasmids, and transfect them into CHO-K1 cells (ATCC CCL-61).
  • the specific transfection and antibody preparation processes are as follows:
  • Cell culture CHO-K1 cells were grown in suspension in ActiPro (GE HyClone) medium, and cultured at 37°C, 7% CO 2 , 140 rpm, and 90% relative humidity;
  • the highly expressed cell fluid cultured in shake flasks was collected and purified by protein A affinity purification (GE, Mab Select SuRe) and ion exchange purification (GE, Capto S).
  • SDS-PAGE and SEC-HPLC were used to analyze the molecular weight and purity of the purified antibody.
  • the results of SDS-PAGE showed that the molecular weight of the prepared hRS7 was as expected, and the purity of the antibody measured by SEC-HPLC was 99.1%.
  • the hRS7 antibody prepared in Example 1 was placed in an ice-water bath in a 10 mg/mL pH 7.4 PBS solution.
  • an equal volume of TCEP solution 3.5 times the amount of the substance was added while stirring and mixing, and the solution was placed 25°C water bath for 1 hour to react.
  • the temperature drops to 25°C then add 7 times the amount of compound A in 40% DMSO solution to the antibody solution while stirring and mixing, and shake the reaction at 25°C for 90 minutes.
  • cysteine was added in an amount 8 times that of the substance, and placed in a water bath at 25° C. for 10 minutes to react to obtain the coupling product ADC-1.
  • DTT dithiothreitol
  • DTT dithiothreitol
  • Embodiment 4 prepares conjugate ADC-3
  • Antibody in 5mg/mL pH 7.4 PBS solution while stirring and mixing, add TCEP solution with 7 times the amount of the substance, and put the solution in a 37°C water bath for 1.5 hours to react. Use a 25°C water bath for the reaction solution. When the temperature drops to 25°C, then add 16 times the amount of compound C in 40% DMSO solution to the antibody solution while stirring and mixing, and shake the reaction at 25°C for 90 minutes. Finally, while the reaction solution was stirred and mixed, cysteine was added in an amount 16 times that of the substance, and placed in a water bath at 25° C. for 10 minutes to react to obtain the coupling product ADC-3.
  • DTT dithiothreitol
  • Embodiment 5 prepares conjugate ADC-4
  • Example 1 The antibody of Example 1 was placed in a 10 mg/mL pH 7.4 PBS solution, using a 25°C water bath, while stirring and mixing, an equal volume of TCEP solution 2.4 times the amount of the substance was added, and the solution was left to stand in a 25°C water bath for 1.5 hours. .
  • Use a 25°C water bath for the sample then add 8 times the amount of compound C in DMSO solution (DMSO final concentration 10%) to the antibody solution while stirring and mixing, shake the reaction at 25°C for 90 minutes, and finally stir and mix the sample
  • 8 times the amount of cysteine was added, and placed in a 25° C. water bath for 10 minutes to react to obtain the coupling product ADC-4.
  • BxPC-3 cells human orthotopic pancreatic adenocarcinoma cells, ATCC CRL-1687
  • the culture conditions were 10% heat-inactivated fetal bovine serum and agar in 1640 medium, at 37°C, containing 5% Culture in an incubator with CO 2 air. Digested with 0.25% trypsin twice a week for passage. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.
  • the P6 tumor tissue was used to evaluate the antitumor activity of the test product.
  • the tumor-bearing mice are anesthetized with CO 2 and killed, the tumor mass is removed, the surrounding necrotic tissue is removed, the tumor mass is cut into small tumor blocks of 20-30 mm 3 , and inoculated to the formal A total of 70 mice were inoculated at the right shoulder blade of the experimental mice.
  • Eighteen days after the tumor block was inoculated when the average tumor volume reached about 135 mm 3 , the mice with too small or too large tumor volume were excluded, and the remaining 50 mice were randomly grouped according to the tumor volume and started to be administered. See the table below for the dosing regimen.
  • QW refers to administration once a week
  • only once refers to no administration after once administration on the day of grouping.
  • tumor volume (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ) (where a represents the long diameter and b represents the short diameter).
  • the relative tumor proliferation rate, T/C% is the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group at a certain time point.
  • tumors were taken from all mice, weighed and photographed.
  • Figures 5-7 The experimental results are shown in Figures 5-7, Figure 5 is the statistical curve of anti-tumor activity, Figure 6 is the curve of body weight change, and Figure 7 is the photograph taken of the tumor.
  • ADC-1 has an excellent tumor-inhibiting effect, and it can completely regress the tumor with only one administration, and it is safe.
  • Colo205 cells human colon cancer cells, ATCC CCL-222 were cultured in a single layer in vitro, and the culture conditions were 10% heat-inactivated fetal bovine serum and agar in 1640 medium, and cultured at 37°C with 5% CO2 air Cultivated in a box. Digested with 0.25% trypsin twice a week for passage. When the cells are in the exponential growth phase, the cells are collected, counted, and inoculated.
  • the P6 tumor tissue was used to evaluate the antitumor activity of the test product.
  • the P5 generation tumor grows to 500-800 mm 3
  • the tumor-bearing mice are anesthetized with CO 2 and killed, the tumor mass is removed, the surrounding necrotic tissue is removed, the tumor mass is cut into small tumor blocks of 20-30 mm 3 , and inoculated to the formal A total of 70 mice were inoculated at the right shoulder blade of the experimental mice.
  • the average tumor volume reached about 135 mm 16 days after tumor block inoculation, the mice with too small or too large tumor volume were excluded, and the remaining 50 mice were randomly grouped according to tumor volume and began to be administered.
  • the dosage regimen is the same as that of the above-mentioned Example 4.
  • tumor volume (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ) (where a represents the long diameter and b represents the short diameter).
  • the relative tumor proliferation rate, T/C% is the percentage value of the relative tumor volume or tumor weight between the treatment group and the control group at a certain time point.
  • tumors were taken from all mice, weighed and photographed.
  • Figure 8 is the statistical curve of anti-tumor activity
  • Figure 9 is the curve of body weight change
  • Figure 10 is the photograph taken of the tumor.
  • Example 5 the Colo205 model was adopted, and all operation steps were referred to in Example 5, and the dosage regimen was shown in the table below.
  • This example adopts the BxPC-3 model, and all operation steps refer to Example 4, and the dosage regimen is shown in the table below.
  • Figure 13 is the statistical curve of anti-tumor activity
  • Figure 14 is the curve of body weight change
  • Figure 15 is the photograph taken of the tumor.

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Abstract

L'invention concerne un conjugué anticorps-médicament à base d'un inhibiteur de microtubules. L'invention concerne spécifiquement un composé tel que représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci, un stéréoisomère de celui-ci, ou un solvate du composé, son sel pharmaceutiquement acceptable ou son stéréoisomère. La présente invention concerne en outre un conjugué anticorps-médicament formé par liaison d'une fraction de ciblage avec le composé tel que représenté par la formule (I), son sel pharmaceutiquement acceptable, son stéréoisomère, ou le solvate du composé, son sel pharmaceutiquement acceptable ou son stéréoisomère par une liaison thioéther. MC-L1-L2-D (I)
PCT/CN2022/112502 2021-08-24 2022-08-15 Conjugué anticorps-médicament conjugué par l'intermédiaire d'un lieur cassable WO2023024949A1 (fr)

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